IP Library › Granted Patent US 12,252,489
Granted Patent B2
US 12,252,489 · App. 17/923,160 · Granted Mar 18, 2025

Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use

Inventors: Lara C. Czabaniuk (Thousand Oaks, CA); Timothy Hopper (Thousand Oaks, CA); Jonathan B. Houze (Cambridge, MA); Gwenaella Rescourio (Thousand Oaks, CA); Vincent Santora (Thousand Oaks, CA); Haoxuan Wang (Thousand Oaks, CA); Ryan D. White (Thousand Oaks, CA); Alice R. Wong (Thousand Oaks, CA); Yongwei Wu (Thousand Oaks, CA)
Assignees: AMGEN Inc.; Vigil Neuroscience, Inc.
C07D471/04A61K31/519A61K31/5377C07D413/14C07D519/00
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,252,489
App. No.
17/923,160
Granted
Mar 18, 2025
Kind
B2
Abstract

The present disclosure provides compounds of Formula (I), useful for the activation of Triggering Receptor Expressed on Myeloid Cells 2 (“TREM2”). This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, a neurodegenerative disorder. Further, the disclosure provides intermediates useful in the synthesis of compounds of Formula (1).

Claims (237)

1. A compound of Formula I

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

X 1 is (1) CH or N and b is a single bond; or (2) C and b is a double bond;

X 2 is CH 2 , CHF, CF 2 , O, or NH;

wherein, optionally, R 5 is absent and the X 2 CR 6 group forms a 5- or 6-membered heteroaryl, wherein the 5-membered heteroaryl contains only one ring atom selected from N, O, and S and optionally only one further N ring atom and wherein the 6 membered heteroaryl contains only one or only two N ring atoms, and wherein said 5- or 6-membered heteroaryl is optionally substituted with halogen, C 1-3 alkyl, or C 1-3 alkoxy;

X 3 at each occurrence independently is CH or N;

R 1 is H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;

R 2 is H, C 1-3 alkyl, C 1-3 haloalkyl, or C 3-6 cycloalkyl;

R 3 is H or C 1-3 alkyl;

R 4 is H or C 1-3 alkyl;

R 5 is H or C 1-3 alkyl;

R 6 is C 2-6 alkyl, C 1-6 haloalkyl, diC 1-3 alkylamino, —C(═O)O(C 1-6 alkyl), C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; wherein

(1) C 3-6 cycloalkyl or C 3-6 heterocycloalkyl is optionally substituted with C═O,

(2) the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —(C 1-3 alkyl)O(C 1-3 alkyl), —(C 1-3 alkyl) NH 2 , —(C 1-3 alkyl) NH (C 1-3 alkyl), —(C 1-3 alkyl)N[(C 1-3 alkyl) (C 1-3 alkyl)], —CN, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl, and C 3-6 heterocycloalkyl; wherein

the C 1-6 alkyl and C 1-6 haloalkyl of subsection (2) are optionally substituted with OH; and wherein

the C 3-6 heterocycloalkyl of subsection (2) is optionally substituted with 1 to 3 substituents selected from halogen, C 1-3 alkyl, and —C(═O)O(C 1-6 alkyl);

R 7 is C 5-6 cycloalkyl, C 5-8 spiroalkyl, C 5-8 tricycloalkyl, phenyl, or 6-membered heteroaryl; wherein R 7 is further optionally substituted with 1 to 4 substituents independently selected from halogen, C 1-3 alkyl, and C 1-3 haloalkyl; and

n is 0 or 1; provided that when X 1 is N and n is 0, X 2 is not NH or O.

2. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound is not

5-(5-chloro-3-methyl-2-pyridinyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-methyl-3-phenyl-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; or

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(1-methyl-1H-imidazol-2-yl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one.

3. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound is a compound of Formula II

or wherein the compound is a compound of Formula IIA

or wherein the compound is a compound of Formula IIB

4. The compound according to claim 3 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

X 1 is CH.

5. The compound according to claim 3 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

X 1 is N.

6. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

X 2 is CH 2 , CF 2 , or O.

7. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the

portion of Formula I is

8. The compound according to claim 3 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

X 3 is CH.

9. The compound according to claim 3 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

X 3 is N.

10. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

R 1 is methyl, ethyl, propyl, —CH 2 CF 3 , cyclopropyl, or cyclohexyl.

11. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

R 2 is H, methyl, trifluoromethyl, or cyclopropyl.

12. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

R 3 is H or methyl.

13. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

R 4 is H or methyl.

14. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

R 5 is H or methyl.

15. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

R 6 is difluoromethyl, trifluoromethyl, —CH 2 CF 3 , dimethylamino, —C(═O) OCH 2 CH 3 , optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted oxetanyl, optionally substituted azetidinyl, optionally substituted tetrahydrofuranyl, optionally substituted pyrrolidinyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted 1,3-oxazolyl, optionally substituted 1,2,4-oxadiazolyl, optionally substituted 1,3,4-oxadiazolyl, optionally substituted thiophenyl, optionally substituted thiazolyl, optionally substituted pyridinyl, optionally substituted pyridazinyl, or optionally substituted pyrimidinyl.

16. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

R 6 is difluoromethyl, trifluoromethyl, —CH 2 CF 3 , dimethylamino, —C(═O) OCH 2 CH 3 , cyclopropyl, cyclobutyl, oxetan-2-yl, azetidine-1-yl, tetrahydrofuran-3-yl,

phenyl,

17. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

R 6 is

18. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

R 7 is optionally substituted C 5-6 cycloalkyl, optionally substituted phenyl, or optionally substituted 6-membered heteroaryl.

19. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

R 7 is

20. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein n is 1.

21. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound is

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4(3H)-quinazolinone;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4(3H)-quinazolinone;

5-(4-chlorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chlorophenyl)-2,3-dimethyl-7-((2R)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-3-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(2,4-difluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(2,3,4-trifluorophenyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(2,4,5-trifluorophenyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2,5-difluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(2-fluoro-4-methylphenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2,3-difluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(5-chloro-3-fluoro-2-pyridinyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4(3H)-quinazolinone;

2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(6-(trifluoromethyl)-3-pyridinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-3-cyclohexyl-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-3-(2,2,2-trifluoroethyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-3-cyclopropyl-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(5-chloro-3-fluoro-2-pyridinyl)-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-3-propylpyrido-[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-ethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(1-ethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,5R)-5-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,5R)-5-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6R)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6R)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-cyclopropyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-(2-cyclobutyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S,6R)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S,6S)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R,6R)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R,6S)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((2R)-2-oxetanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((2S)-2-oxetanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((2S)-2-oxetanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((2R)-2-oxetanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((3S)-tetrahydro-3-furanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((3S)-tetrahydro-3-furanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((3R)-tetrahydro-3-furanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((3R)-tetrahydro-3-furanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(4-pyridazinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-5-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4-(3H)one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-5-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(2,2,2-trifluoroethyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(thiophen-3-yl)morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-thiophenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(2-methyl-4-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-(2-(1,3-dimethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-(2-(5-fluoro-3-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-(2-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6S)-2-methyl-6-(3-thiophenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6R)-2-methyl-6-(3-thiophenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6S)-2-methyl-6-(3-thiophenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6R)-2-methyl-6-(3-thiophenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(4-methyl-1,3-thiazol-2-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2,6-dimethyl-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2,6-dimethyl-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(4-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(4-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(3-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(3-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2-methoxy-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2-methoxy-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(4-chorophenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(4-chorophenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2-chloro-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2-chloro-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

4-(4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)-2-morpholinyl)benzonitrile;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-(trifluoromethyl)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(3-(trifluoromethyl)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(5-phenyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(2-(2,2,2-trifluoroethoxy)-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-(2,2,2-trifluoroethoxy)-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(3-(trifluoromethoxy)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-(trifluoromethoxy)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3S)-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-(3,4-dihydro-2,6-naphthyridin-2(1H)-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(1,3-oxazol-5-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(5-oxo-3-pyrrolidinyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3S)-3-(1H-pyrazol-4-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(1H-pyrazol-4-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-(3-(dimethylamino)-1-piperidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

7-(3-(1-azetidinyl)-1-piperidinyl)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3S)-3-(4-pyridinyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(4-pyridinyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

7-(8-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5′-(4-chloro-2-fluorophenyl)-4-methoxy-2′,3′-dimethyl-7,8-dihydro-5H-[6,7′-bipyrido[4,3-d]pyrimidin]-4′ (3′H)-one;

5-(4-chloro-2-fluorophenyl)-7-((3R)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((3S)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(trifluoromethyl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-(3-(difluoromethyl)-1-pyrrolidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(3-pyridinyl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(2-propanyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(3-oxetanyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1-fluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1-fluoro-2-hydroxyethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1,3-difluoro-2-propanyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

2-methyl-2-propanyl-3-(4-((2S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)-2-morpholinyl)-1H-pyrazol-1-yl)-1-azetidinecarboxylate;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1,2-difluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-ethenyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(1-methyl-3-azetidinyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-2-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-3-ethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-2-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(2,4-difluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

7-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(2,4-difluorophenyl)-3-ethyl-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(5-chloro-3-fluoro-2-pyridinyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-5-yl)-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2R)-2-(1-methyl-1H-pyrazol-5-yl)-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(difluoromethyl)-4-morpholinyl)-2-methyl-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-phenyl-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-cyclohexyl-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-cyclopentyl-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one and 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(6-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

ethyl (2R,4S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate and ethyl (2S,4R)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate;

ethyl (2S,4S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate and ethyl (2R,4R)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(6-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2R,4R)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-7-((2S,4S)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4R)-2-(3-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one and 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4S)-2-(3-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(3-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one; or

5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(3-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one.

22. A pharmaceutical composition comprising the compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.

23. A method of treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, or multiple sclerosis, prion disease, or stroke in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 26, 2024
From: CZABANIUK, LARA C.; HOPPER, TIMOTHY; RESCOURIO, GWENAELLA; SANTORA, VINCENT; WANG, HAOXUAN; WHITE, RYAN D.; WONG, ALICE R.; WU, YONGWEI
To: AMGEN, INC.
Reel/Frame 068097/0190 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 26, 2024
From: HOUZE, JONATHAN B.
To: VIGIL NEUROSCIENCE, INC.
Reel/Frame 068097/0211 →
Continuity (2)
Provisional Application 63019768 · May 4, 2020
Related Publication 20240190863A1 · Jun 13, 2024
References Cited (188)
US 2940972A · Roch · 1960 [cited by applicant]
US 2963481A · Grannells et al. · 1960 [cited by applicant]
US 3712892A · Inaba et al. · 1973 [cited by applicant]
US 5620978A · Cai et al. · 1997 [cited by applicant]
US 7521455B2 · Nagase et al. · 2009 [cited by applicant]
US 7582366B2 · Hwang et al. · 2009 [cited by applicant]
US 7635683B2 · Gai et al. · 2009 [cited by applicant]
US 8084459B2 · Kok et al. · 2011 [cited by applicant]
US 8298825B1 · Hochedlinger et al. · 2012 [cited by applicant]
US 8722692B2 · Che · 2014 [cited by examiner]
US 9905773B2 · Park et al. · 2018 [cited by applicant]
US 10403826B2 · Dyatkin et al. · 2019 [cited by applicant]
US 10573692B2 · Lim et al. · 2020 [cited by applicant]
US 11608344B2 · Czabaniuk et al. · 2023 [cited by applicant]
US 11718617B2 · Czabaniuk et al. · 2023 [cited by applicant]
US 11884675B2 · Czabaniuk et al. · 2024 [cited by applicant]
US 11912711B2 · Czabaniuk et al. · 2024 [cited by applicant]
US 20020161014A1 · Sadhu et al. · 2002 [cited by applicant]
US 20050096327A1 · Caprathe et al. · 2005 [cited by applicant]
US 20070225271A1 · Binggeli et al. · 2007 [cited by applicant]
US 20090099174A1 · Smith et al. · 2009 [cited by applicant]
US 20110124638A1 · Duggan et al. · 2011 [cited by applicant]
US 20130012489A1 · Mederski et al. · 2013 [cited by applicant]
US 20160272632A1 · Childers et al. · 2016 [cited by applicant]
US 20190343838A1 · Allen et al. · 2019 [cited by applicant]
US 20200048207A1 · Parham et al. · 2020 [cited by applicant]
US 20200075870A1 · Boudreault et al. · 2020 [cited by applicant]
US 20200275661A1 · Tamai et al. · 2020 [cited by applicant]
US 20210070792A1 · Shih et al. · 2021 [cited by applicant]
US 20230002390A1 · Czabaniuk et al. · 2023 [cited by applicant]
US 20230144581A1 · Czabaniuk et al. · 2023 [cited by applicant]
US 20230295169A1 · Czabaniuk et al. · 2023 [cited by applicant]
US 20230295170A1 · Czabaniuk et al. · 2023 [cited by applicant]
US 20240124446A1 · Czabaniuk et al. · 2024 [cited by applicant]
US 20240182477A1 · Czabaniuk et al. · 2024 [cited by applicant]
CN 103374021B · 2015 [cited by applicant]
CN 102887895B · 2016 [cited by applicant]
CN 109265457A · 2019 [cited by applicant]
CN 110283171A · 2019 [cited by applicant]
CN 111454265A · 2020 [cited by applicant]
CN 108484680B · 2020 [cited by applicant]
EP 3229290A1 · 2017 [cited by applicant]
IN 2009MU01140A · 2010 [cited by applicant]
JP H05170744A · 1993 [cited by applicant]
JP 2003005355A · 2003 [cited by applicant]
KR 2015080966A · 2015 [cited by applicant]
KR 2016060572A · 2016 [cited by applicant]
KR 2018107604A · 2018 [cited by applicant]
KR 2018116822A · 2018 [cited by applicant]
WO WO1999021840A1 · 1999 [cited by applicant]
WO WO2002058695A1 · 2002 [cited by applicant]
WO WO2004031161A1 · 2004 [cited by applicant]
WO WO2004055013A1 · 2004 [cited by applicant]
WO WO2005007099A2 · 2005 [cited by applicant]
WO WO2005039587A1 · 2005 [cited by applicant]
WO WO2005087742A1 · 2005 [cited by applicant]
WO WO2006039718A2 · 2006 [cited by applicant]
WO WO2006128129A2 · 2006 [cited by applicant]
WO WO2006128172A2 · 2006 [cited by applicant]
WO WO2007038331A2 · 2007 [cited by applicant]
WO WO2007103759A2 · 2007 [cited by applicant]
WO WO2008003149A2 · 2008 [cited by applicant]
WO WO2008130600A2 · 2008 [cited by applicant]
WO WO2009100406A2 · 2009 [cited by applicant]
WO WO2010033906A2 · 2010 [cited by applicant]
WO WO2010042925A2 · 2010 [cited by applicant]
WO WO2010107768A1 · 2010 [cited by applicant]
WO WO2011014039A1 · 2011 [cited by applicant]
WO WO2011037731A1 · 2011 [cited by applicant]
WO WO2011053861A1 · 2011 [cited by applicant]
WO WO2011119565A1 · 2011 [cited by applicant]
WO WO2011156889A1 · 2011 [cited by applicant]
WO WO2013117615A1 · 2013 [cited by applicant]
WO WO2015002729A2 · 2015 [cited by applicant]
WO WO2015017335A1 · 2015 [cited by applicant]
WO WO2015086523A1 · 2015 [cited by applicant]
WO WO2015112806A2 · 2015 [cited by applicant]
WO WO2016166078A1 · 2016 [cited by applicant]
WO WO2017025164A1 · 2017 [cited by applicant]
WO WO2017031427A1 · 2017 [cited by applicant]
WO WO2017181177A1 · 2017 [cited by applicant]
WO WO2018066812A1 · 2018 [cited by applicant]
WO WO2018067704A1 · 2018 [cited by applicant]
WO WO2018108110A1 · 2018 [cited by applicant]
WO WO2018169352A1 · 2018 [cited by applicant]
WO WO2018183923A1 · 2018 [cited by applicant]
WO WO2018195450A1 · 2018 [cited by applicant]
WO WO2018204764A1 · 2018 [cited by applicant]
WO WO2018204765A1 · 2018 [cited by applicant]
WO WO2018227228A1 · 2018 [cited by applicant]
WO WO2019079596A1 · 2019 [cited by applicant]
WO WO2019079607A1 · 2019 [cited by applicant]
WO WO2020231739A2 · 2020 [cited by applicant]
WO WO2021224802A1 · 2021 [cited by applicant]
WO WO2021225968A1 · 2021 [cited by applicant]
WO WO2021226629A1 · 2021 [cited by applicant]
WO WO2023137265A1 · 2023 [cited by applicant]
“SID 378004572 Substance Record: 1265848-98-3,” PubChem. Available Jan. 17, 2019: https://pubchem.ncbi.nlm.nih.gov/substance/378004572. [cited by applicant]
“SID 396338721 Substance Record,” PubChem. Available Dec. 6, 2019: https://pubchem.ncbi.nlm.nih.gov/substance/396338721. [cited by applicant]
Bergner, et al., “Microglia damage precedes major myelin breakdown in X-linked adrenoleukodystrophy and metachromatic leukodystrophy,” Glia. Jun. 2019;67(6):1196-1209. [cited by applicant]
Bianchin, et al., “Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy—PLOSL): a dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects… [cited by applicant]
Bianchin, et al., “Nasu-Hakola disease and primary microglial dysfunction,” Nat Rev Neurol. Sep. 2010;6(9):2 p following 523. [cited by applicant]
Cantoni, et al., “TREM2 regulates microglial cell activation in response to demyelination in vivo,” Acta Neuropathol. Mar. 2015;129(3):429-47. [cited by applicant]
Colonna and Butovsky, “Microglia Function in the Central Nervous System During Health and Neurodegeneration” Annu Rev Immunol. Apr. 26, 2017;35:441-468. [cited by applicant]
Condello, et al., “Microglia constitute a barrier that prevents neurotoxic protofibrillar A(beta)42 hotspots around plaques,” Nat Commun. Jan. 29, 2015;6:6176. [cited by applicant]
Cserép, et al., “Microglia monitor and protect neuronal function through specialized somatic purinergic junctions,” Science. Jan. 31, 2020;367(6477):528-537. [cited by applicant]
Dardiotis, et al., “A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature,” Neurobiol Aging. May 2017;53:194.e13-194.e22. [cited by applicant]
Deming, et al., “The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk, ” Sci Transl Med. Aug. 14, 2019;11(505):eaau2291. [cited by applicant]
Doens and Fernández, “Microglia receptors and their implications in the response to amyloid beta for Alzheimer's disease pathogenesis,” J Neuroinflammation. Mar. 13, 2014;11:48. [cited by applicant]
Domingues, et al., “Oligodendrocyte, Astrocyte, and Microglia Crosstalk in Myelin Development, Damage, and Repair,” Front Cell Dev Biol. Jun. 28, 2016;4:71. [cited by applicant]
Ewers, et al., “Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer's disease,” Sci Transl Med. Aug. 28, 2019;11(507):eaav6221. [cited by applicant]
Filipello, et al., “The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity,” Immunity. May 15, 2018;48(5):979-991.e8. [cited by applicant]
Golde, et al., “Alzheimer's disease risk alleles in TREM2 illuminate innate immunity in Alzheimer's disease,” Alzheimers Res Ther. May 21, 2013;5(3):24. [cited by applicant]
Gong, et al., “Microglial dysfunction as a key pathological change in adrenomyeloneuropathy,” Ann Neurol. Nov. 2017;82(5):813-27. [cited by applicant]
Guerreiro, et al., “TREM2 variants in Alzheimer's disease,” N Engl J Med. Jan. 10, 2013;368(2):117-27. [cited by applicant]
Guerreiro, et al., “Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement,” JAMA Neurol. Jan. 2013;70(1):78-84. [cited by applicant]
Guo, et al., “TREM2 deficiency aggravates -synuclein-induced neurodegeneration and neuroinflammation in Parkinson's disease models,” FASEB J. Nov. 2019;33(11):12164-12174. [cited by applicant]
Hickman and El Khoury, “Analysis of the Microglial Sensome,” Methods Mol Biol. 2019;2034:305-323. [cited by applicant]
Hickman, et al., “Microglia in neurodegeneration,” Nat Neurosci. Oct. 2018;21(10):1359-1369. [cited by applicant]
Hickman, et al., “Microglia in neurodegeneration,” Nat Neurosci. 2018;21(10):1359-1369. [cited by applicant]
Hickman, et al., “The microglial sensome revealed by direct RNA sequencing,” Nat Neurosci. Oct. 27, 2013;16(12):1896-1905. [cited by applicant]
Hollingworth, et al., “Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease,” Nat Genet. May 2011;43(5):429-35. [cited by applicant]
Hong, et al., “New insights on the role of microglia in synaptic pruning in health and disease,” Curr Opin Neurobiol. Feb. 2016;36:128-34. [cited by applicant]
Hori, et al., “Novel 4-phenoxy-2-(1-piperazinyl)quinazolines as potent anticonvulsive and antihypoxic agents,” Chem Pharm Bull (Tokyo). Mar. 1990;38(3):681-7. [cited by applicant]
Huang and Pope, “The role of toll-like receptors in rheumatoid arthritis,” Curr Rheumatol Rep. Oct. 2009;11(5):357-64. [cited by applicant]
Ikegami, et al., “Microglia: Lifelong modulator of neural circuits,” Neuropathology. Jun. 2019;39(3):173-180. [cited by applicant]
Jaitin, et al., “Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner,” Cell. Jul. 25, 2019;178(3):686-698.e14. [cited by applicant]
Jay, et al., “TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models,” J Exp Med. Mar. 9, 2015;212(3):287-95. [cited by applicant]
Jay, et al., “TREM2 in Neurodegenerative Diseases,” Mol Neurodegener. Aug. 2, 2017;12(1):56. [cited by applicant]
Jonsson, et al., “Variant of TREM2 associated with the risk of Alzheimer's disease, ” N Engl J Med. Jan. 10, 2013;368(2):107-16. [cited by applicant]
Kang, et al., “Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal,” Hum Mol Genet. Jan. 15, 2018;27(2):211-223. [cited by applicant]
Keren-Shaul, et al., “A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease,” Cell. Jun. 15, 2017;169(7):1276-1290.e17. [cited by applicant]
Kim, et al., “Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects,” Mol Psychiatry. Nov. 2017;22(11):1576-1584. [cited by applicant]
Kleinberger, et al., “TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis,” Sci Transl Med. Jul. 2, 2014;6(243):243ra86. [cited by applicant]
Kobayashi, et al., “TREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain,” J Neurosci. Oct. 26, 2016;36(43):11138-11150. [cited by applicant]
Kober and Brett, “TREM2-Ligand Interactions in Health and Disease,” J Mol Biol. Jun. 2, 2017;429(11):1607-1629. [cited by applicant]
Konno, et al., “CSFIR-related leukoencephalopathy: A major player in primary microgliopathies”, Neurology, Dec. 11, 2018;91(24):1092-1104. [cited by applicant]
Lee, et al., “Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models,” Neuron. Mar. 7, 2018;97(5):1032-1048.e5. [cited by applicant]
Leyns, et al., “TREM2 function impedes tau seeding in neuritic plaques,” Nat Neurosci. Aug. 2019;22(8):1217-1222. [cited by applicant]
Li and Barres, “Microglia and macrophages in brain homeostasis and disease,” Nat Rev Immunol. Apr. 2018;18(4):225-242. [cited by applicant]
Liddelow, et al., “Neurotoxic reactive astrocytes are induced by activated microglia,” Nature. Jan. 26, 2017;541(7638):481-487. [cited by applicant]
Madry and Attwell, “Receptors, ion channels, and signaling mechanisms underlying microglial dynamics,” J Biol Chem. May 15, 2015;290(20):12443-50. [cited by applicant]
Madry, et al., “Nasu-Hakola disease (PLOSL): report of five cases and review of the literature,” Clin Orthop Relat Res. Jan. 2007;454:262-9. [cited by applicant]
Oosterhof, et al., “Colony-Stimulating Factor 1 Receptor (CSF1R) Regulates Microglia Density and Distribution, but Not Microglia Differentiation In Vivo,” Cell Rep. Jul. 31, 2018;24(5):1203-1217. [cited by applicant]
Otero, et al., “TREM2 and beta-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis,” J Immunol. Mar. 15, 2012;188(6):2612-21. [cited by applicant]
Paloneva, et al., “DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features,” J Exp Med. Aug. 18, 2003;198(4):669-75. [cited by applicant]
Paolicelli, et al., “Synaptic pruning by microglia is necessary for normal brain development,” Science. Sep. 9, 2011;333(6048):1456-8. [cited by applicant]
Parhizkar, et al., “Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE,” Nat Neurosci. Feb. 2019;22(2):191-204. [cited by applicant]
PCT International Search Report and Written Opinion from PCT/US2021/030719, dated Aug. 20, 2021. [cited by applicant]
PCT International Search Report and Written Opinion from PCT/US2021/070507 dated Jun. 30, 2021. [cited by applicant]
PCT International Search Report and Written Opinion from PCT/US2022/072095, dated Aug. 25, 2022. [cited by applicant]
Peng, et al., “TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1,” Sci Signal. May 18, 2010;3(122):ra38. [cited by applicant]
Rademakers, et al,. “Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids,” Nat Genet. 2012;44(2):200-5. [cited by applicant]
Schlepckow, et al., “Enhancing Protective Microglial Activities With a Dual Function TREM2 Antibody to the Stalk Region,” EMBO Mol Med. Apr. 7, 2020;12(4):e11227. [cited by applicant]
Sellgren, et al., “Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning, ” Nat Neurosci. Mar. 2019;22(3):374-385. [cited by applicant]
Shinozaki, et al., “Transformation of Astrocytes to a Neuroprotective Phenotype by Microglia via P2Y1 Receptor Downregulation,” Cell Rep. May 9, 2017;19(6):1151-1164. [cited by applicant]
Shirotani, et al., “Aminophospholipids are signal-transducing TREM2 ligands on apoptotic cells,” Sci Rep. May 17, 2019;9(1):7508. [cited by applicant]
Sims, et al., “Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial- mediated innate immunity in Alzheimer's disease,” Nat Genet. Sep. 2017;49(9):1373-1384. [cited by applicant]
Spangenberg, et al., “Sustained microglial depletion with CSFIR inhibitor impairs parenchymal plaque development in an Alzheimer's disease model,” Nat Commun. 2019;10:3758. [cited by applicant]
Suárez-Calvet, et al., “Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-beta pathology,” Mol Neurodegener. Jan. 10, 2019;14(1):1. [cited by applicant]
Tang, et al., “Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits,” Neuron. Sep. 3, 2014;83(5):1131-43. [cited by applicant]
Ulland, et al., “TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease,” Cell. Aug. 10, 2017;170(4):649-663.e13. [cited by applicant]
Ulrich and Holtzman, “TREM2 Function in Alzheimer's Disease and Neurodegeneration,” ACS Chem Neurosci. Apr. 20, 2016;7(4):420-7. [cited by applicant]
Ulrich, et al., “Elucidating the Role of TREM2 in Alzheimer's Disease,” Neuron. Apr. 19, 2017;94(2):237-248. [cited by applicant]
Wang, et al., “TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model,” Cell. Mar. 12, 2015;160(6):1061-71. [cited by applicant]
Wang, et al., “Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model”, J Exp Med. Sep. 7, 2020;217(9):e20200785. [cited by applicant]
Weinhofer, et al., “Impaired plasticity of macrophages in X-linked adrenoleukodystrophy,” Brain. Aug. 1, 2018;141(8):2329-2342. [cited by applicant]
Wu, et al., “TREM2 protects against cerebral ischemia/reperfusion injury,” Mol Brain. Jun. 7, 2017;10(1):20. [cited by applicant]
Yeh, et al., “TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia,” Neuron. Jul. 20, 2016;91(2):328-40. [cited by applicant]
Yuan, et al., “TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy,” Neuron. May 18, 2016;90(4):724-39. [cited by applicant]
Co-pending, U.S. Appl. No. 18/309,281, inventors Czabaniuk, L., et al., filed Apr. 28, 2023 (Not yet Published). [cited by applicant]
Co-pending, U.S. Appl. No. 18/472,147, inventors Czabaniuk, L., et al., filed Sep. 21, 2023 (Not yet Published). [cited by applicant]
Wilen, et al., “Strategies in optical resolutions,” Tetrahedron May 3, 1977; 33(21): 2725-2736. [cited by applicant]
Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci. Jan. 1977; 66(1): 1-19. [cited by applicant]
Hayes, S., [cited by applicant]
Lieberman, H. A., et al., eds., [cited by applicant]
Kibbe, A. H., ed., [cited by applicant]
Tovey, G. D., ed., [cited by applicant]
Sorrell, T. N., [cited by applicant]
Smith, M. B., and March, J., [cited by applicant]
Jacques, J., et al.,. “Resolution of alcohols, ” in [cited by applicant]
Eliel, E. L., [cited by applicant]
Wilen, S. H., [cited by applicant]
Stahl, P. H., and Wermuth, C. G., eds., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd revised edition, Wiley-VCH, Weinheim, Germany, 2011. [cited by applicant]
Miller, M., et al. “Identification of ML204, a Novel Potent Antagonist That Selectively Modulates Native TRPC4/C5 Ion Channels,” J Biol Chem 286(38):33436-33446, Elsevier, Netherlands (Sep. 2011). [cited by applicant]
Zhao, H., and Jin, J., “Visible Light-Promoted Aliphatic C—H Arylation Using Selectfluor as a Hydrogen Atom Transfer Reagent,” Org Lett 21(16):6179-6184, American Chemical Society, United States (Aug. 2019). [cited by applicant]
Wuyts, B., et al., “Biopharmaceutical profiling of a pyrido[4,3-d] pyrimidine compound library,” Int J Pharm 455(1-2):19-30, Elsevier, Netherlands (Oct. 2013). [cited by applicant]
Xu, T., “The role of myeloid cell-triggered receptor 2 in neurodegenerative diseases,” Journal of Apolexy and Neurological Diseases 36(11):1053-1056, Jilin Dayijingcheng Media Co., China (Nov. 2019). [cited by applicant]